Process for production of optically active compounds

ABSTRACT

The present invention provides a method for producing an optically active β-hydroxy ester compound represented by the general formula: 
                         
wherein
         R 1  represents an optionally substituted hydrocarbon group and the like,   R 2  represents a nitrogen-containing heterocyclic group different from R 1 , which is represented by the general formula:       
                         
wherein the ring may be substituted and the like,
         R 3  represents an optionally substituted hydrocarbon group and the like,   R 4  and R 5  represent, the same or different, a hydrogen atom, a halogen atom and the like,   the symbol “*” represents an optically active center, which comprises reacting in the presence of a cinchona alkaloid and the like a compound represented by the general formula:       
                         
wherein R 1  and R 2  are as defined above with a compound represented by the general formula:
 
                         
wherein R 3 , R 4  and R 5  are as defined above, and X is a halogen atom.

This application is the National Phase filing of International PatentApplication No. PCT/JP03/02563, filed Mar. 5, 2003.

TECHNICAL FIELD

The present invention relates to a method for producing optically activeβ-hydroxy esters useful in producing pharmaceuticals, agrichemicals,liquid crystals and raw materials therefor.

BACKGROUND ART

In optically active compounds, particularly those used aspharmaceuticals, it is not rare to find that bioactivity,pharmacokinetics, pharmacodynamics, toxicity and the like are differentbetween optical isomers. Therefore, it is required to resolve orseparately synthesize optical isomers not only in test and developmentstages and also in actual production.

An optically active β-hydroxy ester has high versatility as aningredient for pharmaceuticals or a raw material therefor and, thus,studies on a method for producing it are continued.

A reaction between aldehyde or ketone and a reagent prepared fromα-haloester and zinc, a so-called Reform at sky reaction, is extremelyuseful as a method for producing β-hydroxy esters because of its highversatility. However, such a reaction has not been established as amethod for producing optically active compounds. Particularly, highstereoselectivity has not been achieved in a reaction with ketone asdescribed in, for example, J. Chem. Soc., Chem. Commun., 1993, 811;Tetrahedron, 1973, 29, 3659; and Tetrahedron, 1997, 53 (10), 3787. Inaddition, a stereoselective Reformatsky reaction using an asymmetricligand in a reaction with ketone having a heterocyclic ring has neverbeen studied.

If a Reformatsky reaction were proceeded streoselectively, an opticallyactive β-hydroxy ester would be obtained. Since a Reformatsky reactionallows coexisting of functional groups such as ester, amide and thelike, it will be a high versatile method. Particularly, since there isno practical method for producing optically active tertiary alcoholswhich are obtained by a reaction with ketone, a high yield and highversatile method for producing them is desired.

DISCLOSURE OF THE INVENTION

The present inventors made every effort in view of the above situationand, as a result, found that high stereoselectivity can be achieved inthe presence of a cinchona alkaloid or a salt thereof when R² in ketoneor aldehyde represented by the general formula (I) is anitrogen-containing heterocyclic group, which resulted in completion ofthe present invention.

That is, the present invention relates to:

-   (1) A method for producing an optically active β-hydroxy ester    compound represented by the general formula:

wherein

-   -   R¹ represents a hydrogen atom, an optionally substituted        hydrocarbon group, or an optionally substituted heterocyclic        group,    -   R² represents a nitrogen-containing heterocyclic group different        from R¹, which is represented by the general formula:

wherein the ring may be substituted, and may have one or moreheteroatoms in addition to the nitrogen atom in the formula, and mayhave one or more double bonds in addition to the double bond in theformula; or the general formula:

wherein the ring may be substituted, and may have one or moreheteroatoms in addition to the nitrogen atom in the formula, and mayhave one or more double bonds in addition to the double bond in theformula, provided that a case is eliminated where R¹ is an optionallysubstituted aromatic group and R² is a group represented by the generalformula:

wherein L represents a protecting group,

-   -   R³ represents an optionally substituted hydrocarbon group or an        optionally substituted heterocyclic group,    -   R⁴ and R⁵ are the same or different, and represent a hydrogen        atom, a halogen atom, an optionally substituted silyl group, an        optionally substituted hydrocarbon group or an optionally        substituted heterocyclic group, and (1) R³ and R⁴, (2) R³ and        R⁵, or (3) R⁴ and R⁵ may be taken together to form a ring,        wherein said ring may be substituted,    -   the symbol “*” represents an optically active center, or a salt        thereof, which comprises reacting, in the presence of a cinchona        alkaloid or a salt thereof, a compound represented by the        general formula:

wherein R¹ and R² are as defined above or a salt thereof with a compoundrepresented by the general formula:

wherein R³, R⁴ and R5 are as defined above, and X is a halogen atom, ora polymer thereof or a salt thereof;

-   (2) The method according to (1), which further comprises adding a    base;-   (3) The method according to (2), wherein the base is pyridine;-   (4) The method according to (1), wherein the cinchona alkaloid is    cinchonine, cinchonidine, quinine, or qunidine;-   (5) The method according to (1), wherein R² is an optionally    substituted 2-pyridyl group or 4-imidazolyl group; and-   (6) The method according to (1), wherein R¹ is a hydrogen atom, an    optionally substituted aliphatic hydrocarbon group, or an optionally    substituted heterocyclic group, and R² is a group different from R¹,    which is represented by the general formula:

wherein L represents a protecting group.

BEST MODE FOR CARRYING OUT THE INVENTION

R¹ in the general formula (I) and R³, R⁴ and R⁵ in the general formula(II) represent a hydrogen atom, an optionally substituted hydrocarbongroup, or an optionally substituted heterocyclic group.

For the hydrocarbon group in the “optionally substituted hydrocarbongroup” represented by R¹, R³, R⁴ and R⁵, for example, an “aliphaticchain hydrocarbon group”, an “alicyclic hydrocarbon group” and an“aromatic hydrocarbon group” may be used.

For the “aliphatic chain hydrocarbon group” representing a hydrocarbongroup, for example, a linear- or branched-chain aliphatic hydrocarbongroup such as an alkyl group, an alkenyl group, an alkynyl group and thelike may be used.

For the “alkyl group”, for example, a C₁₋₁₀ alkyl group such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl,n-heptyl, 1-methyheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl, nonyland the like may be used. Preferably, a C₁₋₆ alkyl group (e.g., methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.) andthe like may be used.

For the “alkenyl group”, for example, a C₂₋₁₀ alkenyl group such asvinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl and the like may be used. Preferably, aC₂₋₆ alkenyl group and the like may be used.

For the “alkynyl group”, for example, a C₂₋₁₀ alkynyl group such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like may be used. Preferably, aC₂₋₆ alkynyl group and the like may be used.

For the “alicyclic hydrocarbon group” representing a hydrocarbon group,for example, a saturated or unsaturated monocyclic or fused polycyclicalicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenylgroup, a cycloalkanedienyl group, a di- or tri-cyclic fused ring of theaforementioned groups and a C₆₋₁₄ aryl group (e.g., benzene etc.) andthe like may be used.

For the “cycloalkyl group”, for example, a C₃₋₁₀ cycloalkyl group suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptylcyclooctyl, cyclononyl and the like may be used.

For the “cycloalkenyl group”, for example, a C₃₋₁₀ cycloalkenyl groupsuch as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the likemay be used.

For the “cycloalkanedienyl group”, for example, a C₄₋₆ cycloalkanedienylgroup such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl and the like may be used.

For the “aromatic hydrocarbon group” representing a hydrocarbon group, amonocyclic or fused polycyclic aromatic hydrocarbon group may be used.The aromatic hydrocarbon group is not limited, but is preferably a C₆₋₂₂aromatic hydrocarbon group, more preferably a C₆₋₁₈ aromatic hydrocarbongroup, further preferably a C₆₋₁₀ aromatic hydrocarbon group.Specifically, for example, phenyl, o-tolyl, m-tolyl, p-tolyl, 2,3-xylyl,2,4-xylyl, mesityl, o-cumenyl, m-cumenyl, p-cumenyl, α-methylbenzyl,benzhydryl, o-biphenyl, m-biphenyl, p-biphenylel, 1-naphthyl,2-naphthyl, 2-indenyl, 2-anthryl, azurenyl, phenathryl, fluorenyl andthe like may be used. Among them, pheyl, 1-naphthyl, 2-naphthyl,2-anthryl and the like are preferred.

For the aliphatic hydrocarbon group in the “optionally substitutedaliphatic hydrocarbon group” represented by R¹, the same groups as thosedefined above may be used.

For the heterocyclic group in the “optionally substituted heterocyclicgroup” represented by R¹, R³, R⁴ and R⁵, for example, an aromaticheterocyclic group and a saturated or unsaturated non-aromaticheterocyclic group (an aliphatic heterocyclic group) having one to threekinds (preferably one or two kinds) of at least one (preferably one tofour, and more preferably one or two) heteroatoms selected from anoxygen atom, a sulfur atom, a nitrogen atom and the like as an atomconstituting the ring (an atom on the ring) may be used. Theheterocyclic group is not limited, but is preferably a 5- to 22-memberedheterocyclic group, more preferably a 5- to 18-membered heterocyclicgroup, further preferably a 5- to 14-membered heterocyclic group, andstill further preferably a 5- to 10-membered heterocyclic group.

Specifically, examples of the “aromatic heterocyclic group” include a 5-or 6-membered monocyclic aromatic heterocyclic group (e.g., 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, thiazolyl, 3-isothiazolyl,4-isothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,1-pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 3-pyridazinyl, 2-pyrimidinyl, pyrazinyl, triazinyl, etc.) anda 8- to 12-membered fused aromatic heterocyclic group (e.g.,benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl,1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl,benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl,quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl,α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.). Preferably, a heterocyclicgroup in which the above 5- or 6-membered monocyclic aromaticheterocyclic group is fused with a benzene ring or a heterocyclic groupin which two same or different heterocyclic rings from the above 5- or6-membered monocyclic aromatic heterocyclic group are fused may be used.

Specifically, examples of the “non-aromatic heterocyclic group” includea 3- to 8-membered (preferably, 5- or 6-membered) saturated orunsaturated (preferably saturated) non-aromatic heterocyclic group (analiphatic heterocyclic group) such as pyrrolinyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, quinuclidinyl, aziridinyl,oxiranyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, tetrahydropyranyl,2-dioxolanyl, 2-thiazanyl, 3-thiazanyl, 2-morpholinyl, 3-morpholinyl,thiomorpholinyl, 2-piperazinyl and the like may be used.

R² represents a nitrogen-containing heterocyclic group different fromR¹, which is represented by the general formula (V):

wherein the ring may be substituted, and may have one or moreheteroatoms in addition to the nitrogen atom in the formula, and mayhave one or more double bonds in addition to the double bond in theformula; or the general formula (VI):

wherein the ring may be substituted, and may have one or moreheteroatoms in addition to the nitrogen atom in the formula, and mayhave one or more double bonds in addition to the double bond in theformula.

The nitrogen-containing heterocyclic ring represented by the generalformula (V) or (VI) may contain one to three kinds (preferably one ortwo kinds) of one or more (preferably one to four, more preferably oneor two) heteroatoms selected from an oxygen atom, a sulfur atom, anitrogen atom and the like in addition to the nitrogen atom in theformula, and may have one or more double bonds in addition to the doublebond in the formula. For the substituent which the nitrogen-containingheterocyclic group represented by the general formula (V) or (VI) mayhave, the same number of the same group as the substituent in an“optionally substituted heterocyclic group” defined below may be used.

Specifically, as the nitrogen-containing heterocyclic ring representedby the general formula (V) or (VI), a 5- or 6-membered monocyclicnitrogen-containing aromatic heterocyclic group such as 3H-pyrrol-2-yl,2H-pyrrol-5-yl, 2H-pyrrol-2-yl, 3H-pyrrol-5-yl, 1H-imidazol-4-yl,4H-imidazol-4-yl, 2H-imidazol-4-yl, 4H-imidazol-5-yl, 4H-imidazol-2-yl,1H-imidazol-2-yl, 1H-imidazol-3-yl, 2H-imidazol-2-yl, 4H-imidazol-2-yl,3-oxazol-4-yl, 1,3-oxazol-2-yl, isoxazol-3-yl, 1H-pyrazol-3-yl,3H-pyrazol-5-yl, 4H-pyrazol-3-yl, 1,3,4-oxadiazol-2-yl,1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-S-yl, 1,2,3-oxadiazol-4-yl,1,2,4-oxadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,4-thiadiazol-3-yl,1,3-thiazol-4-yl, 1,3-thiazol-2-yl, isothiazol-3-yl,1H-1,2,3-triazol-4-yl, 3H-1,2,4-triazol-5-yl, 3H-1,2,4-triazol-3-yl,2H-tetrazol-2-yl, 2H-tetrazol-5-yl, 1H-tetrazol-5-yl, 2-pyridyl,pyridazin-3-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl,1,2,3-triazin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-6-yl,1,2,4-triazin-5-yl, 1,2,4-triazin-3-yl and the like and a 8- to12-membered fused nitrogen-containing aromatic heterocyclic group suchas 3H-indol-2-yl, 2H-isoindol-2-yl, 2H-isoindol-1-yl, quinolin-2-yl,isoquinolin-1-yl, isoquinolin-3-yl, 7H-purin-8-yl, 9H-purin-8-yl,7H-purin-6-yl, 9H-purin-6-yl, 9H-purin-2-yl, 7H-purin-2-yl,1H-indazol-3-yl, quinazolin-2-yl, quinazolin-4-yl, cinnolin-3-yl,quinoxalin-2-yl, phthalazin-1-yl, pteridin-2-yl, pteridin-4-yl,pteridin-6-yl, pteridin-7-yl, 7H-imidazo[4,5-c]pyridazin-3-yl,5H-imidazo[4,5-c]pyridazin-3-yl, 7H-imidazo[4,5-c]pyridazin-6-yl,5H-imidazo[4,5-c]pyridazin-6-yl, 1H-pyrazolo[3,4-b]pyridin-6-yl,3H-pyrazolo[3,4-b]pyridin-6-yl, 3H-pyrazolo[3,4-b]pyridin-3-yl,1,3-benzoxazol-2-yl, 1,2-benzoxazol-3-yl, 1,3-benzothiazol-2-yl,1,2-benzothiazol-3-yl, 1H-1,2,3-benzotriazol-1-yl,3H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c] pyridin-2-yl,3H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-5-yl,3H-imidazo[4,5-c]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,3H-imidazo[4,5-c]pyridin-4-yl, 1H-imidazo[4,5-c]pyridin-4-yl,3H-imidazo[4,5-c]pyridin-6-yl, 1H-imidazo[4,5-c]pyridin-6-yl,phenanthridin-6-yl may be used. A heterocyclic ring in which the above5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclicgroup is fused with a benzene ring and a heterocyclic group in which twosame or different heterocyclic rings from the above 5- or 6-memberedmonocyclic nitrogen-containing aromatic heterocyclic group are fused arealso preferred. Further, for example, a 3- to 8-membered (preferably 5-or 6-membered) unsaturated nitrogen-containing aliphatic heterocyclicgroup such as 3,4-dihydro-2H-pyrrol-5-yl, 3,4-dihydro-2H-pyrrol-2-yl,4,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-4-yl,2,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl,4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-3H-pyrazol-3-yl,2,5-dihydro-1,3-thiazol-2-yl, 4,5-dihydro-1,3-thiazol-2-yl,2,5-dihydro-1,3-thiazol-4-yl, 4,5-dihydro-1,3-thiazol-4-yl,4,5-dihydro-1,3-thiazol-3-yl, 2,5-dihydro-1,3-oxazol-2-yl,4,5-dihydro-1,3-oxazol-2-yl, 2,5-dihydro-1,3-oxazol-4-yl,4,5-dihydro-1,3-oxazol-4-yl, 4,5-dihydro-1,3-oxazol-3-yl and the likemay be used.

The halogen atom represented by X, R⁴ and R⁵ are chlorine, bromine oriodine, and bromine and iodine are preferred.

Herein, for the ring in a phrase “(1) R³ and R⁴, (2) R³ and R⁵, or (3)R⁴ and R⁵ may be taken together to form a ring, wherein said ring may besubstituted”, an “alicyclic hydrocarbon”, an “aromatic hydrocarbon”, a“heterocyclic ring such as an aromatic heterocyclic ring and anon-aromatic heterocyclic ring” and the like may be used.

For the “alicyclic hydrocarbon”, for example, a saturated or unsaturatedmonocyclic or fused polycyclic alicyclic hydrocarbon such ascycloalkane, cycloalkene, cycloalkanediene, and a di- or tri-cyclicfused ring of the aforementioned groups nd a C₆₋₁₄ aryl (e.g., benzeneetc.) may be used.

For the “cycloalkane”, for example, C₃₋₁₀ cycloalkane such ascyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, cyclononane and the like may be used.

For the “cycloalkene”, for example, C₃₋₁₀ cycloalkene such ascyclopentene, cyclohexene, cyclobuten and the like may be used.

For the “cycloalkanediene”, for example, C₄₋₆ cycloalkanediene such ascyclopentadiene, cyclohexadiene, cyclohexanediene and the like may beused.

For the “aromatic hydrocarbon”, a monocyclic or fused polycyclicaromatic hydrocarbon may be used without any limitation. Preferably aC₆₋₂₂ aromatic hydrocarbon, more preferably a C₆₋₁₈ aromatichydrocarbon, and further preferably a C₆₋₁₀ aromatic hydrocarbon may beused. Specifically, examples of the aromatic hydrocarbon includebenzene, toluene, xylene, mesitylene, cumene, styrene,1,2,3-trimethylbenzene, pentalene, indene, naphthalene, azulene,heptalene, biphenylene, benzocyclohepten, as-indacene, s-indacene,acenaphthylene, fluorene, phenalene, phenenthrene, anthracene,fluoranthene, acephenanthrylene, aceanthrylene, triphenylene, pyrene,chrysene, naphthacene and the like. Among them, benzene, toluene,naphthalene and the like are preferred.

For the “heterocyclic ring”, for example, an aromatic heterocyclic ringand a saturated or unsaturated non-aromatic heterocyclic ring (analiphatic heterocyclic ring) having one to three kinds (preferably oneor two kinds) of at least one (preferably one to four, and morepreferably one or two) heteroatoms selected from an oxygen atom, asulfur atom, a nitrogen atom and the like as an atom constituting thering (an atom on the ring) may be used. The heterocyclic ring is notlimited, but is preferably a 5- to 22-membered heterocyclic ring, morepreferably a 5-to 18-membered heterocyclic ring, further preferably a 5-to 14-membered heterocyclic ring, and still further preferably a 5- to10-membered heterocyclic ring.

Specifically, examples of the “aromatic heterocyclic ring” include a 5-or 6-membered monocyclic aromatic heterocyclic ring (e.g., furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine, etc.) and a 8- to12-membered fused aromatic heterocyclic ring (e.g., benzofuran,isobenzofuran, benzothiophene, indole, isoindole, indazole,benzindazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, benzopyran,1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline,cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine,pteridine, carbazole, α-carboline, β-carboline, γ-carboline, acridine,phenoxazine, phenothiazine, phenazine, phenoxathiine, thianthrene,phenanthridine, phenanthroline, indolizine, pyrrolo[1,2-b]pyridazine,pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine,imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrimidine,1,2,4-triazolo[4,3-a]pyridine, 1,2,4-triazolo[4,3-b]pyridazine, etc.)may be used. Preferably, a heterocyclic group in which the above 5- or6-membered monocyclic aromatic heterocyclic group is fused with abenzene ring and a heterocyclic group in which two same or differentheterocyclic rings from the above 5- or 6-membered monocyclic aromaticheterocyclic group are fused may be used.

Specifically, examples of the “non-aromatic heterocyclic ring” include a3- to 8-membered (preferably, 5- or 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic ring (an aliphaticheterocyclic ring) such as pyrroline, imidazoline, imidazolidine,pyrazoline, pyrazolidine, quinuclidine, aziridine, oxirane, azetidine,pyrrolidine, tetrahydrofuran, thiolane, piperidine, tetrahydropyran,dioxolane, thiazane, morpholine, thiomorpholine, piperazine and thelike.

The cinchona alkaloid is, for example, cinchonine, cinchonidine,quinine, or quinidine.

In the present invention, examples of the substituent from the“optionally substituted hydrocarbon group”, the “optionally substitutedheterocyclic group”, the “optionally substituted aromatic group”, the“optionally substituted aliphatic hydrocarbon group”, a phrase “(1) R³and R⁴, (2) R³ and R⁵, or (3) R⁴ and R⁵ may be taken together to form aring, wherein said ring may be substituted” or a phrase “the ring may besubstituted, and may have one or more heteroatoms in addition to thenitrogen atom in the formula, and may have one or more double bonds inaddition to the double bond in the formula” include but are not limitedto (i) an optionally substituted alkyl group; (ii) an optionallysubstituted alkenyl group; (iii) an optionally substituted alkynylgroup; (iv) an optionally substituted aryl group; (v) an optionallysubstituted aralkyl group; (vi) an optionally substituted cycloalkylgroup; (vii) an optionally substituted cycloalkenyl group; (viii) anoptionally substituted heterocyclic group; (ix) an optionallysubstituted amino group; (x) an optionally substituted hydroxyl group;(xi) an optionally substituted thiol group; (xii) an optionallysubstituted alkylsulfinyl group; (xiii) an optionally esterified oramidated carboxyl group; (xiv) an optionally substituted thiocarbamoylgroup; (xv) an optionally substituted sulfamoyl group; (xvi) a halogenatom (e.g., fluorine, chlorine, bromine, iodine, etc., and preferablychlorine, bromine, etc.); (xvii) a cyano group; (xviii) an isocyanogroup; (xix) a cyanate group; (xx) an isocyanate group; (xxi) athiocyanate group; (xxii) an isothiocyanate group; (xxiii) a nitrogroup; (xxiv) a nitroso group; (xxv) an acyl group derived from sulfonicacid; and the like. These optional substituents may bind to one to five,preferably one to three replaceable positions. Additionally, when thereare two or more substituents, they may be the same or different fromeach other.

For the alkyl group in the “optionally substituted alkyl group” as thesubstituent, for example, C₁₋₆ alkyl such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl and the like may be used. Examples of the substituentof the alkyl group include a lower alkoxyl group (e.g., C₁₋₆ alkoxy suchas methoxy, ethoxy, propoxy, etc.), a halogen atom (e.g., fluorine,chlorine, bromine, iodine, etc.), a lower alkyl group (e.g., C₁₋₆ alkylsuch as methyl, ethyl, propyl, etc.), a lower alkenyl group (e.g., C₂₋₆alkenyl such as vinyl, allyl, etc.), a lower alkynyl group (e.g.,C₂₋₆alkynyl such as ethynyl, propargyl, etc.), an optionally substitutedamino group, an optionally substituted hydroxyl group, a cyano group, anoptionally substituted amidino group, a carboxyl group, a loweralkoxycarbonyl group (e.g., C₁₋₆ alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, etc.), an optionally substituted carbamoyl group (e.g.,methylcarbamoyl etc.), a 5- or 6-membered monocyclic aromaticheterocyclic group (e.g., pyridyl etc.) and the like. These optionalsubstituents may bind to one to three replaceable positions.

For the “optionally substituted amino group”, the “optionallysubstituted hydroxyl group” and the “optionally substituted amidinogroup” as a substituent for the “optionally substituted alkyl group”,the same group as an “optionally substituted amino group”, an“optionally substituted hydroxyl group and an “optionally substitutedamidino group” as a substituent for an “optionally substituted aromaticring or heterocyclic ring” mentioned below may be used.

For the alkenyl group in the “optionally substituted alkenyl group” as asubstituent, for example, C₂₋₆ alkenyl such as vinyl, allyl,isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl and the like may be used. For the substituent in the alkenylgroup, the same number of the same group as the substituent in the“optionally substituted alkyl group” as a substituent may be used.

For the alkynyl group in the above “optionally substituted alkynylgroup” as a substituent, for example, C₂₋₆ alkynyl such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl and the like may be used. For the substituent inthe alkynyl group, the same number of the same group as the substituentin the “optionally substituted alkyl group” as a substituent may beused.

For the aryl group in the “optionally substituted aryl group” as asubstituent, for example, C₆₋₁₄ aryl such as phenyl, naphthyl, anthryl,phenanthryl, acenaphthyrenyl and the like may be used. For thesubstituent in the aryl group, the same number of the same group as thesubstituent in the “optionally substituted alkyl group” as a substituentmay be used.

For the aralkyl group in the “optionally substituted aralkyl group” as asubstituent, for example, C₇₋₁₁ aralkyl such as benzyl, phenethyl,naphthylmethyl and the like may be used. For the substituent in thearalkyl group, the same number of the same group as the substituent inthe “optionally substituted alkyl group” as a substituent may be used.

For the cycloalkyl group in the “optionally substituted cycloalkylgroup” as a substituent, for example, C₃₋₇ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike may be used. For the substituent in the cycloalkyl group, the samenumber of the same group as the substituent in the “optionallysubstituted alkyl group” as a substituent may be used.

For the cycloalkenyl group in the “optionally substituted cycloalkenylgroup” as a substituent, for example, C₃₋₇ cycloalkenyl such ascyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the likemay be used. For the substituent in the cycloalkenyl group, the samenumber of the same group as the substituent in the “optionallysubstituted alkyl group” as a substituent may be used.

For the heterocyclic group in the “optionally substituted heterocyclicgroup” as a substituent, for example, an aromatic heterocyclic group anda saturated or unsaturated non-aromatic heterocyclic group (an aliphaticheterocyclic group) having one to three kinds (preferably one or twokinds) of at least one (preferably one to four, and more preferably oneor two) heteroatoms selected from an oxygen atom, a sulfur atom, anitrogen atom and the like as an atom constituting the ring (an atom onthe ring) may be used.

For the “aromatic heterocyclic group”, a 5- or 6-membered monocyclicaromatic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl and the like and a 8- to 12-memberedfused polycyclic aromatic heterocyclic group such as benzofuranyl,isobenzofuranyl, benzo[b] thienyl, indolyl, isoindolyl, 1H-indazolyl,benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and thelike may be used.

For the “non-aromatic heterocyclic group”, a 3- to 8-membered(preferably, 5- or 6-membered) saturated or unsaturated (preferablysaturated) non-aromatic heterocyclic group (an aliphatic heterocyclicgroup) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl and the like or a non-aromatic heterocyclicgroup in which a part or all of double bonds in the above monocyclicaromatic heterocyclic group or fused polycyclic aromatic heterocyclicgroup are saturated such as 1,2,3,4-tetrahydroquinolyl,1,2,3,4-tetrahydroisoquinolyl and the like may be used.

For the substituent which the “optionally substituted heterocyclicgroup” as a substituent may have, a lower alkyl group (e.g., C₁₋₆ alkylsuch as methyl, ethyl, propyl, etc.), a lower alkenyl group (e.g., C₂₋₆alkenyl such as vinyl, allyl, etc.), a lower alkynyl group (e.g., C₂₋₆alkynyl such as ethynyl, propargyl, etc.), an optionally substitutedamino group, an optionally substituted hydroxyl group, a halogen atom(e.g., fluorine, chlorine, bromine), an optionally substituted imidoylgroup, an optionally substituted amidino group and the like may be used.These optional substituents may bind to one to five, preferably one tothree replaceable positions.

For the “optionally substituted amino group”, the “optionallysubstituted hydroxyl group” and the “optionally substituted amidinogroup” which the “optionally substituted heterocyclic group” as asubstituent may have, the same group as an “optionally substituted aminogroup”, an “optionally substituted hydroxyl group”, an “optionallysubstituted imidoyl group” and an “optionally substituted amidino group”as a substituent in an “optionally substituted aromatic homocyclic orheterocyclic group” mentioned below may be used.

For the substituent in the “optionally substituted amino group”, the“optionally substituted amidino group”, the “optionally substitutedhydroxyl group” and the “optionally substituted thiol group” as asubstituent, for example, a lower alkyl group (e.g., C₁₋₆ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,hexyl, etc.) which may be substituted with a substituent selected from ahalogen atom (e.g., fluorine, chlorine, bromine, etc.), optionallyhalogenated C₁₋₆ alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2-trichloroethoxy, etc.)and a C₇₋₁₁ alkylaryl group (e.g., o-toluyl, m-toluyl, p-toluyl, xylyl,mesityl, etc., preferably C₁₋₅ alkylphenyl etc.); an acyl group (C₁₋₆alkanoyl (e.g., formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl,C₁₋₆ alkylsulfonyl (e.g., methanesulfonyl etc.), benzenesulfonyl, etc.);an optionally halogenated C₁₋₆ alkoxycarbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, etc.); a C₁₋₆ alkoxycarbonyl group whichmay be substituted with a phenyl group (e.g., benzyloxycarbonyl etc.);aryl (e.g., C₆₋₁₀ aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.);aralkyl (e.g., C₇₋₁₀ aralkyl such as benzyl, phenethyl, etc., preferablyphenyl-C₁₋₄ alkyl etc.); arylalkenyl (e.g., C₈₋₁₀ arylalkenyl such ascinnamyl etc., preferably phenyl-C₂₋₄alkenyl etc.) and a heterocyclicgroup (the same group as the heterocyclic group in the “optionallysubstituted heterocyclic group” as a substituent may be used, and theseoptional substituents may bind to one to three replaceable positions.)may be used.

The “amino group” in the “optionally substituted amino group” as asubstituent may be substituted with one or two C₁₋₆ alkyl groups. Theseoptional substituents may bind to one or two replaceable positions. Inaddition, two substituents may be taken together with a nitrogen atom toform a cyclic amino group. As such a cyclic amino group, for example, a3- to 8-membered (preferably 5- or 6-membered) cyclic amino group suchas 1-azetidinyl; 1-pyrrolidinyl; piperidino; thiomorpholino; morpholino;1-piperazinyl which may have lower alkyl (e.g., C₁₋₆ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl,etc.), aralkyl (e.g., C₇₋₁₀ aralkyl such as benzyl, phenethyl, etc.), oraryl (e.g., C₆₋₁₀ aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.) atthe 4-position; 1-pyrrolyl; 1-imidazolyl and the like may be used.

For the alkylsulfinyl group in the “optionally substituted alkylsulfinylgroup” as a substituent, C₁₋₆ alkylsulfinyl such as methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl,hexylsulfinyl and the like may be used. For the substituent in thealkylsulfinyl, the same number of the same group as the substituent inthe “optionally substituted alkyl group” as a substituent may be used.

For the “optionally esterified or amidated carboxyl group” as asubstituent, a carboxyl group, alkoxycarbonyl, aryloxycarbonyl,aralkyloxycarbonyl, carbamoyl, N-monosubstituted carbamoyl andN,N-disubstituted carbamoyl may be used.

For the “alkoxycarbonyl”, for example, C₁₋₆ alkoxycarbonyl (loweralkoxycarbonyl) such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl and the like may be used.Among them, C₁₋₃ alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and the like are preferred. The “lower alkoxycarbonyl”may have a substituent and, for the substituent, a hydroxyl group; anoptionally substituted amino group [the amino group may have one or twosubstituents such as a lower alkyl group (e.g., C₁₋₆ alkyl suchasmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,hexyl, etc., preferably methyl, ethyl, etc.) which may be substitutedwith one to five halogen atoms (e.g., fluorine, chlorine, bromine,iodine, etc.); an acyl group (e.g., C₁₋₆ alkanoyl such as formyl,acetyl, propionyl, pivaloyl, etc.; benzoyl etc.); a carboxyl group; C₁₋₆alkoxycarbonyl; etc.]; a halogen atom (e.g., fluorine, chlorine,bromine, etc.); a nitro group; a cyano group; a lower alkoxyl group(e.g., C₁₋₆ alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., preferably methoxy,ethoxy, etc.) which may be substituted with one to five halogen atoms(e.g., fluorine, chlorine, bromine, iodine, etc.) may be used. Thesesubstituents are the same or different and, preferably, one, two orthree (preferably one or two) of them bind to.

For the “aryloxycarbonyl”, for example, C₆₋₁₄ aryloxycarbonyl such asphenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl,1-phenanthoxycarbonyl and the like are preferred. The “aryloxycarbonyl”may have a substituent and, for the substituent, the same number of thesame group as the substituent in the “alkoxycarbonyl” as a substituentmay be used.

For the “aralkyloxycarbonyl”, for example, C₇₋₁₄ aralkyloxycarbonyl(preferably C₆₋₁₀ aryl-C₁₋₄ alkoxy-carbonyl etc.) such asbenzyloxycarbonyl, phenethyloxycarbonyl and the like are preferred. The“aralkyloxycarbonyl” may have a substituent and, for the substituent,the same number of the same group as the substituent in the“alkoxycarbonyl” as a substituent may be used.

The “N-monosubstituted carbamoyl” means a carbamoyl group which has onesubstituent on a nitrogen atom and, for the substituent, for example,lower alkyl (e.g., C₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.); lower alkenyl (e.g.,C₂₋₆ alkenyl such as vinyl, allyl, isopropenyl, propenyl, butenyl,pentenyl, hexenyl, etc.); cycloalkyl (e.g., C₃₋₆ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.); aryl (e.g.,C₆₋₁₀ aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.); aralkyl (e.g.,C₇₋₁₀ aralkyl such as benzyl, phenethyl, etc., preferably phenyl-C₁₋₄alkyl etc.); arylalkenyl (e.g., C₈₋₁₀ arylalkenyl such as cinnamyl etc.,preferably phenyl-C₂₋₄ alkenyl etc.); a heterocyclic group (e.g., thesame group as the “heterocyclic group” in the “optionally substitutedheterocyclic group” as a substituent etc.) and the like may be used. Thelower alkyl, the lower alkenyl, the cycloalkyl, the aryl, the aralkyl,the arylalkenyl and the heterocyclic group may have a substituent and,for the substituent, the same number of the same group as thesubstituent in the alkoxycarbonyl as a substituent may be used.

The “N,N-disubstituted carbamoyl” means a carbamoyl group which has twosubstituents on a nitrogen atom, as an example of one substituent, thesame group as the substituent in the “N-monosubstituted carbamoyl” as asubstituent may be used and, as an example for the other substituent,for example, lower alkyl (e.g., C₁₋₆ alkyl such as methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,etc.), C₇₋₁₀ aralkyl (e.g., benzyl, phenethyl, etc., preferablyphenyl-C₁₋₄ alkyl etc.) and the like may be used. In addition, twosubstituents may be taken together with a nitrogen atom to form a cyclicamino group. As such cyclic aminocarbamoyl, for example, a 3- to8-membered (preferably 5- or 6-membered) cyclic aminocarbonyl such as1-azetidinylcarbonyl; 1-pyrrolidinylcarbonyl; piperidinocarbonyl;morpholinocarbonyl; 1-piperazinylcarbonyl; and 1-piperazinylcarbonylwhich may have lower alkyl (e.g., C₁₋₆ alkyl such as methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), aralkyl(e.g., C₇₋₁₀ aralkyl such as benzyl, phenethyl, etc.), or aryl (e.g.,C₆₋₁₀ aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.) at the4-position may be used.

For the substituent in the “optionally substituted thiocarbamoyl group”and the “optionally substituted sulfamoyl group” as a substituent, thesame group as the substituent for the “N-monosubstituted carbamoyl” andthe “N,N-disubstituted carbamoyl” in the “optionally esterified oramidated carboxyl group” as a substituent may be used.

For the “acyl derived from sulfonic acid” as a substituent, for example,a group in which one substituent on the nitrogen atom in theN-monosubstituted carbamoyl is coupled with sulfonyl may be used and,preferably acyl derived from C₁₋₆ alkylsulfonyl such as methanesulfonyl,ethanesulfonyl and the like may be used.

For the substituent in the “optionally substituted silyl group”represented by R⁴ and R⁵, the same number of the same group as thesubstituent in the “optionally substituted alkyl group” as a substituentmay be used. Specifically, for example, a trimethylsilyl group, atert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, atriphenylsilyl group and the like may be used.

The symbol “*” represents herein an optically active center (a chiralcenter).

R¹ and R² are as defined above, provided that a case is eliminated fromthe present invention where R¹ is an optionally substituted aromaticgroup and R² is a group represented by the general formula (IV):

wherein L represents a protecting group.

The “optionally substituted aromatic group” represented by R¹ is amonocyclic or fused bicyclic aromatic group which may be substitutedwith one or more substituents. Specifically, examples include phenyl,1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, azulenyl, phenanthryl,phenalenyl, fluorenyl, indacenyl, biphenylenyl, heptalenyl,acenaphthylenyl and the like. Among them, phenyl, 1-naphthyl,2-naphthyl, 1-anthryl and 2-anthryl are preferred. For the substituent,the same number of the same group as the substituent in the “optionallysubstituted aryl group” as a substituent may be used.

The protecting group represented by L is a protecting group for an aminoacid and, specifically, examples include formyl, and C₇₋₁₀aralkyloxymethyl (benzyloxymethyl etc.), C₁₋₆ alkylcarbonyloxymethyl(tert-butylcarbonyloxymethyl etc.), C₆₋₁₂ arylsulfonyl (p-toluensulfonyletc.), and di-C₁₋₄ alkylaminosulfonyl, and trityl, each of which may besubstituted. As the substituent for them, a halogen atom (fluorine,chlorine, bromine, iodine), C₁₋₆alkyl-carbonyl (acetyl, propionyl,valeryl, etc.), and a nitro group may be used. The number of thesubstituents is one to three.

For R², particularly, optionally substituted 2-pyridyl or optionallysubstituted 4-imidazolyl (wherein for the substituents, the same numberof the same group as the substituent which the “optionally substitutedheterocyclic group” as a substituent may have may be used) arepreferred, and particularly 2-pyridyl and 4-imidazolyl are preferred.

For R³, particularly methyl, ethyl tert-butyl, menthyl and the like arepreferred.

For R⁴, particularly hydrogen, fluorine, bromine, methyl, ethyl, propyl,butyl, benzyl and the like are preferred.

For R⁵, particularly hydrogen, fluorine, bromine, methyl, ethyl, propyl,butyl, benzyl and the like are preferred.

The method according to the present invention can be carried out asdescribed below.

wherein each symbol is as defined above.

The compound represented by the general formula (II) may be produced byreacting α-haloester and zinc according to a method described in, forexample, Jikken Kagaku Kouza, vol. 25, 4th ed., p. 72, Chem. Soc. Japan,Maruzen, 1992. Powder-, flake-, and wool-like zinc may be used. Thesecan be activated by diluted hydrochloric acid treatment and the likeprior to use. Further, trimethylsilyl chloride or dibromoethane may beadded at a catalytic amount.

A reaction of the compound represented by the general formula (I) andthe compound represented by the general formula (II) is generallycarried out in a solvent.

Any solvent may be used as far as it does not affect the reaction and,for example, a hydrocarbon solvent (e.g., hexane, pentane, cyclohexane),an amide solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone), an aromatic hydrocarbon solvent (e.g., toluene,benzene), an aliphatic ester solvent (e.g., ethylacetate, propylacetate), an ether solvent (e.g., diehtyl ether, diisopropyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane), a halogenatedhydrocarbon solvent (e.g., chloroform, dichloromethane,1,2-dichloroethane) and the like may be used. These solvents may be usedalone or mixed in any combination thereof. Particularly,tetrahydrofuran, diethyl ether, benzene and toluene are preferred. Anamount of the solvent to be used is generally about 1 to about 1000parts by volume, preferably about 5 to about 100 parts by volumerelative to an amount of the compound represented by the general formula(I).

A reaction temperature is about −100° C. to about 100° C., preferablyabout −50° C. to about 50° C.

A reaction time is not limited, but is 1 minute to 50 hours, preferably10 minutes to 10 hours.

An amount of the compound represented by the general formula (II) to beused is about 0.5 to about 10 equivalents, preferably about 1 to about10 equivalents relative to an amount of the compound represented by thegeneral formula (I).

The cinchona alkaloid is, for example, cinchonine, cinchonidine,quinine, or qunidine. An amount to be used is about 0.5 to about 10equivalents, preferably about 1 to about 3 equivalents, more preferablyabout 1 to about 2 equivalents relative to an amount of the compoundrepresented by the general formula (I).

In the method of the present invention, addition of a base improvesyield and stereoselectivity in some cases. As the base, an organic baseis preferably used. Examples of the organic base include but are notlimited to triethylamine, trimethylamine, diisopropylethylamine,pyridine, picoline, dimethylaminopyridine, ethanolamine, diethanolamine,dicyclohexylamine, quinoline and the like. Preferablydiisopropylethylamine, quinoline and pyridine, more preferablydiisopropylethylamine and pyridine, further preferably pyridine may beused.

An amount of the base to be used is about 0.1 to about 10 equivalents,preferably about 0.5 to about 5 equivalents, more preferably about 1 toabout 4 equivalents relative to an amount of the compound represented bythe general formula (I).

Timing for adding the base into the reaction system is not limited, butthe base may be added at any time as far as it does not affect thereaction. Preferably, the base is added after the compound representedby the general formula (II) and the cinchona alkaloid are mixed into thereaction solvent. More preferably, the base is added 1 minute to 30minutes after mixing of the compound represented by the general formula(II) and the cinchona alkaloid into the reaction solvent.

The optically active β-hydroxy ester represented by the general formula(III) thus obtained may be further isolated and purified by using theknown method such as solvent extraction, solvent exchange,re-dissolution into another solvent, salting out, crystallization,recrystallization, chromatography and the like.

The compound represented by the general formula (I), (II) or (III) mayform a salt thereof. The salt of the compound is not limited as far asit does not affect the reaction. For example, a salt with an inorganicbase, an ammonium salt, a salt with an organic base, a salt with aninorganic acid, a salt with an organic acid and a salt with an aminoacid may be used. Preferable examples of the salt with an inorganic baseinclude an alkali metal salt such as a sodium salt, a potassium salt andthe like; an alkaline earth metal salt such as a calcium salt, amagnesium salt and the like; an aluminum salt; an ammonium salt; and thelike. Preferable examples of the salt with an organic base include saltswith trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like. Preferableexamples of the salt with an inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferable examples of the salt with anorganic acid include salts with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferable examples of the salt with a basic amino acidinclude salts with arginine, lysine, ornithine and the like. Preferableexamples of the salt with an acidic amino acid include salts withaspartic acid, glutamic acid and the like.

The optically active β-hydroxy ester or a salt thereof obtainedaccording to the present invention is useful as pharmaceuticals,agrichemicals, liquid crystals, and raw materials therefor.

EXAMPLES AND REFERENCE EXAMPLES

The following Examples and Reference Examples illustrate the presentinvention in more detail, but the present invention is not limited tothem.

Nuclear magnetic resonance spectra (¹H-NMR) were measured usingtetramethylsilane as an internal standard on JMTCO400/54 (400 MHz)manufactured by JEOL. Ltd., and δ values are reported in ppm.

Symbols used in Examples mean as follows:

-   s: singlet, d: doublet, t: triplet, m: multiplet, br: broad, J:    coupling constant, TFA: trifluoroacetic acid, ^(t)Bu: tert-butyl,    Tr: trityl.

Infrared absorption spectra (IR) were measured on Paragon 1000manufactured by PerkinElmer, Inc.

Enantiomer excesses (% ee) were measured with high performance liquidchromatography. Columns for high performance liquid chromatography(CHIRALPAK AD, CHIRALCEL OD, CHIRALCEL OJ) were purchased from DicelChemical Industries Ltd.

Example 1 tert-butyl3-hydroxy-4-methyl-3-(1-trityl-1H-imidazol-4-yl)pentanoate

Under argon atmosphere, cinchonine (440 mg, 1.0 mmol) was suspended intetrahydrofuran (absolute, 2.0 mL), and to this suspension was added aReformatsky reagent (0.5 M; 8.0 mL, 4.0 mmol) dropwise underice-cooling. After stirring for 10 minutes, pyridine (0.30 mL, 2 mmol)was added thereto dropwise. After stirring for 20 minutes underice-cooling, the mixture was cooled to −40° C. A solution of2-methyl-1-(1-trityl-1H-imidazol-4-yl)propan-1-one (1.0 mmol) intetrahydrofuran (absolute, 4.0 mL) was added dropwise over 10 minutes,and the mixture was stirred at −40° C. for 4 hours. To this reactionsolution was added 1N HCl (20 mL), which was then extracted with ethylacetate (20 mL×2). The extracted solution was washed successively withan aqueous saturated sodium bicarbonate solution and an aqueoussaturated sodium chloride solution. After the organic layer was driedwith sodium sulfate, the solvent was removed under reduced pressure. Theresidue was analyzed with high performance liquid chromatography.Consequently, the yield was 73% and the enantiomer excess was 94%.

¹H NMR (400 MHz, CDCl₃) δ: 0.84 (3H, d, J=6.9 Hz), 0.88 (3H, d, J=6.9Hz), 1.37 (9H, s), 1.94–2.05 (1H, m), 2.66 (1H, d, J=15.6 Hz), 3.01 (1H,d, J=15.6 Hz), 4.57 (1H, s), 6.79 (1H, s), 7.0–7.2 (6H, m), 7.2–7.4(10H, m).

IR (KBr) νcm⁻¹: 3453, 2978, 1693, 1446, 1365, 1335, 1150, 951, 819, 749,700.

High Performance Liquid Chromatography

Column: CHIRALPAK AD

Mobile phase: Hexane/Ethanol (95/5)

Flow rate: 0.5 mL/min.

Detection: UV (254 nm)

Temperature: Room Temperature

Retention Time: 35.4 minutes (enantiomer 15.6 minutes)

Example 2 tert-butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propionate

Under argon atmosphere, cinchonine (220 mg, 0.5 mmol) was suspended intetrahydrofuran (absolute, 1.0 mL), and to this suspension was added aReformatsky reagent (0.52 M; 7.7 mL, 1.51 mmol) dropwise underice-cooling. After stirring for 10 minutes, pyridine (0.15 mL, 2 mmol)was added thereto dropwise. After stirring for 20 minutes underice-cooling, the mixture was cooled to −40° C. A solution of4-formyl-1-trityl-1H-imidazole (0.5 mmol) in tetrahydrofuran (absolute,2.0 mL) was added dropwise over 10 minutes, and the mixture was stirredat −40° C. for 4 hours. To this reaction solution was added 1N HCl (10mL), which was then extracted with ethyl acetate (10 mL×2). Theextracted solution was washed successively with an aqueous saturatedsodium bicarbonate solution and an aqueous saturated sodium chloridesolution. After the organic layer was dried with sodium sulfate, thesolvent was removed under reduced pressure. The residue was analyzedwith high performance liquid chromatography. Consequently, the yield was84% and the enantiomer excess was 66%.

¹H NMR (400 MHz, CDCl₃) δ: 1.42 (9H, s), 2.74 (1H, dd, J=16.4 and 7.8Hz), 2.81 (1H, dd, J=16.4 and 4.6 Hz), 3.42 (1H, d, J=4.9 Hz), 5.06 (1H,m), 6.79 (1H, s), 7.1–7.2 (7H, m), 7.29–7.36 (8H, m), 7.37 (1H, d, J=1.4Hz).

IR (KBr) νcm⁻¹: 3197, 2974, 1726, 1493, 1444, 1148, 701.

High Performance Liquid Chromatography

Column: CHIRALPAK AD

Mobile phase: Hexane/2-Propanol (90/10)

Flow rate: 1.0 mL/min.

Detection: UV (220 nm)

Temperature: 30° C.

Retention Time: 22.5 minutes (enantiomer 16.8 minutes)

Example 3 tert-butyl 3-hydroxy-3-phenyl-3-(pyridin-2-yl)propionate

Under argon atmosphere, cinchonine (440 mg, 1.0 mmol) was suspended intetrahydrofuran (absolute, 2.0 mL), and to this suspension was added aReformatsky reagent (0.5 M; 8.0 mL, 4.0 mmol) dropwise underice-cooling. After stirring for 10 minutes, pyridine (0.30 mL, 2 mmol)was added thereto dropwise. After stirring for 20 minutes underice-cooling, the mixture was cooled to −40° C. A solution of2-benzoylpyridine (183 mg, 1.0 mmol) in tetrahydrofuran (absolute, 4.0mL) was added dropwise over 10 minutes, and the mixture was stirred at−40° C. for 4 hours. To this reaction solution was added 1N HCl (20 mL),which was then extracted with ethyl acetate (20 mL×2). The extractedsolution was washed successively with an aqueous saturated sodiumbicarbonate solution and an aqueous saturated sodium chloride solution.After the organic layer was dried with sodium sulfate, the solvent wasremoved under reduced pressure. The residue was analyzed with highperformance liquid chromatography. Consequently, the yield was 98% andthe enantiomer excess was 90%.

¹H NMR (400 MHz, CDCl₃) δ: 1.32 (9H, s), 3.12 (1H, d, J=15.8 Hz), 3.52(1H, d, J=15.8 Hz), 5.51 (1H, s), 7.1–7.3 (4H, m), 7.5–7.7 (4H, m), 8.5(1H, m).

IR (neat) νcm⁻¹: 3461, 2978, 1702, 1368, 1154, 700.

High Performance Liquid Chromatography

Column: CHIRALCEL OJ

Mobile phase: Hexane/Ethanol (975/25)

Flow rate: 1.0 mL/min.

Detection: UV (220 nm)

Temperature: 30° C.

Retention Time: 12.0 minutes (enantiomer 14.4 minutes)

Example 4 tert-butyl3-hydroxy-3-(4-chlorophenyl)-3-(pyridin-2-yl)propionate

Under argon atmosphere, cinchonine (440 mg, 1.0 mmol) was suspended intetrahydrofuran (absolute, 2.0 mL), and to this suspension was added aReformatsky reagent (0.5 M; 8.0 mL, 4.0 mmol) dropwise underice-cooling. After stirring for 10 minutes, pyridine (0.30 mL, 2 mmol)was added thereto dropwise. After stirring for 20 minutes underice-cooling, the mixture was cooled to −40° C. A solution of2-(4-chlorobenzoyl)pyridine (218 mg, 1.0 mmol) in tetrahydrofuran(absolute, 4.0 mL) was added dropwise over 10 minutes, and the mixturewas stirred at −40° C. for 4 hours. To this reaction solution was added1N HCl (20 mL), which was then extracted with ethyl acetate (20 mL×2).The extracted solution was washed successively with an aqueous saturatedsodium bicarbonate solution and an aqueous saturated sodium chloridesolution. After the organic layer was dried with sodium sulfate, thesolvent was removed under reduced pressure. The residue was analyzedwith high performance liquid chromatography. Consequently, the yield was81% and the enantiomer excess was 91%.

¹H NMR (400 MHz, CDCl₃) δ: 1.33 (9H, s), 3.08 (1H, d, J=16.0 Hz), 3.49(1H, d, J=16.0 Hz), 5.52 (1H, s), 7.1–7.7 (7H, m), 8.4–8.6 (1H, m).

IR (KBr) νcm⁻¹: 3358, 2977, 1694, 1591, 1490, 1467, 1368, 1159, 1090,1013, 830, 785, 755, 591.

High Performance Liquid Chromatography

Column: CHIRALCEL OJ

Mobile phase: Hexane/Ethanol/Trifluoroacetic acid (99/1/0.1)

Flow rate: 0.5 mL/min.

Detection: UV (254 nm)

Temperature: Room Temperature

Retention Time: 24.5 minutes (enantiomer 17.3 minutes)

Example 5 tert-butyl 3-hydroxy-3-(pyridin-2-yl)butanoate

Under argon atmosphere, cinchonine (440 mg, 1.0 mmol) was suspended intetrahydrofuran (absolute, 2.0 mL), and to this suspension was added aReformatsky reagent (0.5 M; 8.0 mL, 4.0 mmol) dropwise underice-cooling. After stirring for 10 minutes, pyridine (0.30 mL, 2 mmol)was added thereto dropwise. After stirring for 20 minutes underice-cooling, the mixture was cooled to −40° C. A solution of2-acetylpyridine (120 mg, 1.0 mmol) in tetrahydrofuran (absolute, 4.0mL) was added dropwise over 10 minutes, and the mixture was stirred at−40° C. for 4 hours. To this reaction solution was added 1N HCl (20 mL),which was then extracted with ethyl acetate (20 mL×2). The extractedsolution was washed successively with an aqueous saturated sodiumbicarbonate solution and an aqueous saturated sodium chloride solution.After the organic layer was dried with sodium sulfate, the solvent wasremoved under reduced pressure. The residue was analyzed with highperformance liquid chromatography. Consequently, the yield was 94% andthe enantiomer excess was 86%.

¹H NMR (400 MHz, CDCl₃) δ: 1.30 (9H, s), 1.53 (3H, s), 2.73 (1H, d,J=15.5 Hz), 3.10 (1H, d, J=15.5 Hz), 4.95 (1H, s), 7.1 (1H, m), 7.6–7.7(2H, m), 8.5 (1H, m).

IR (KBr) νcm⁻¹: 3477, 2979, 1704, 1591, 1472, 1434, 1392, 1368, 1228,1159, 1107, 793, 751.

High Performance Liquid Chromatography

Column: CHIRALPAK AD

Mobile phase: Hexane/Ethanol (975/25)

Flow rate: 0.5 mL/min.

Detection: UV (220 nm)

Temperature: Room Temperature

Retention Time: 17.4 minutes (enantiomer 15.8 minutes)

Example 6 tert-butyl 3-hydroxy-3-(pyridin-2-yl)propionate

Under argon atmosphere, cinchonine (440 mg, 1.0 mmol) was suspended intetrahydrofuran (absolute, 2.0 mL), and to this suspension was added aReformatsky reagent (0.4 M; 10.0 mL, 4.0 mmol) dropwise underice-cooling. After stirring for 10 minutes, pyridine (0.30 mL, 2 mmol)was added thereto dropwise. After stirring for 20 minutes underice-cooling, the mixture was cooled to −40° C. A solution of2-pyridinecarbaldehyde (108 mg, 1.0 mmol) in tetrahydrofuran (absolute,4.0 mL) was added dropwise over 10 minutes, and the mixture was stirredat −40° C. for 4 hours. To this reaction solution was added 1N HCl (20mL), which was then extracted with ethyl acetate (20 mL×2). Theextracted solution was washed successively with an aqueous saturatedsodium bicarbonate solution and an aqueous saturated sodium chloridesolution. After the organic layer was dried with sodium sulfate, thesolvent was removed under reduced pressure. The residue was analyzedwith high performance liquid chromatography. Consequently, the yield was94% and the enantiomer excess was 70%.

¹H NMR (400 MHz, CDCl₃) δ: 1.44 (9H, s), 2.65–2.72 (1H, m), 2.81–2.87(1H, m), 4.27 (1H, d, J=4.9 Hz), 5.13 (1H, m), 7.1–7.3 (1H, m) 7.4 (1H,d, J=6.8 Hz), 7.6–7.8(1H, m), 8.54 (1H, d, J=3.0 Hz).

IR (neat) νcm⁻¹: 2979, 1727, 1594, 1368, 1152.

High Performance Liquid Chromatography

Column: CHIRALPAK AD

Mobile phase: Hexane/Ethanol (95/5)

Flow rate: 1.0 mL/min.

Detection: UV (220 nm)

Temperature: 30° C.

Retention Time: 20.1 minutes (enantiomer 18.0 minutes)

INDUSTRIAL APPLICABILITY

According to the method of the present invention, optically activeβ-hydroxy esters or salts thereof which is useful as pharmaceuticals,agrichemicals, liquid crystals, and raw materials therefor can beobtained easily at high optical purities and, thus, the method is veryuseful industrially.

1. A method for producing an optically active β-hydroxy ester compoundrepresented by the general formula:

wherein R¹ represents an optionally substituted aromatic hydrocarbongroup, R² represents a 5- or 6-membered nitrogen-containing heterocyclicgroup which is represented by the general formula:

wherein the ring may be substituted, and may have one or moreheteroatoms selected from the group consisting of an oxygen atom, asulfur atom and a nitrogen atom in addition to the nitrogen atom in theformula, and may have one or more double bonds in addition to the doublebond in the formula; or the general formula:

wherein the ring may be substituted, and may have one or moreheteroatoms selected from the group consisting of an oxygen atom, asulfur atom and a nitrogen atom in addition to the nitrogen atom in theformula, and may have one or more double bonds in addition to the doublebond in the formula, provided that R² is not a group represented by thegeneral formula:

wherein L represents a protecting group, R³ represents an optionallysubstituted hydrocarbon group, R⁴ and R⁵ are the same or different, andrepresent a hydrogen atom, or an optionally substituted hydrocarbongroup, or R⁴ and R⁵ may be taken together to form a ring, wherein saidring may be substituted, the symbol “*” represents an optically activecenter, or a salt thereof, which comprises reacting, in the presence ofa cinchona alkaloid selected from the group consisting of cinchonine,cinchonidine, quinine and quinidine or a salt thereof, a compoundrepresented by the general formula:

wherein R¹ and R² are as defined above or a salt thereof with a compoundrepresented by the general formula:

wherein R³, R⁴ and R⁵ are as defined above, and X is a halogen atom, ora polymer thereof or a salt thereof.
 2. The method according to claim 1,which further comprises adding a base.
 3. The method according to claim2, wherein the base is pyridine.
 4. The method according to claim 1,wherein R² is an optionally substituted 2-pyridyl group or 4-imidazolylgroup.